FAQ

What is Genetic Testing for HHT?

Genetic testing for HHT consists of studying the endoglin and ALK-1 genes. It is a specialized type of testing performed in only a few laboratories worldwide. The goal is to find the exact DNA change (mutation) believed to be responsible for HHT in a given family. This process (called sequencing) involves extensive analysis of the genetic code of these two known HHT genes. Once such a mutation has been found in one family member who has a diagnosis of HHT, other family members can be tested to see if they also have this 'family specific' HHT mutation. This can allow us to say with a high level of certainty which other family members have inherited HHT. But - there are frequently complexities and uncertainties involved with HHT genetic testing. It often isn't simply a 'yes or no' answer.

Why Is Genetic Testing Useful? If I Already Know That I Have HHT, Why Should I Have Genetic Testing?

If a person already knows that he or she has HHT because of the clinical diagnostic criteria, genetic testing can confirm the diagnosis. (The clinical diagnostic criteria are listed at the end of this section.) Also, knowing which gene is involved can help to predict the likelihood of certain manifestations associated with HHT.

Often the primary reason that genetic testing is useful for someone already diagnosed with HHT is to help other family members in whom the diagnosis of HHT is not certain. Children and young adults with HHT often do not have visible symptoms of HHT yet, but are still at risk for complications from lung AVMs and brain AVMs from the time of birth. Since we recommend specific medical screening tests to detect AVMs as early in life as possible for all individuals with HHT- it is important to know at a young age which family members have actually inherited the HHT gene. In families where an endoglin or ALK-1 gene mutation has already been identified in a family member with HHT, testing other family members for this known mutation will allow the physician to identify which children and other family members really need these medical screening tests to prevent serious complications of HHT such as stroke or brain abscess.

How Is Genetic Testing Done?

Genetic testing is done on a blood sample - shipped to one of the laboratories performing genetic testing for HHT. It is not a type of testing familiar to most primary care doctors and there are only 1 or 2 laboratories per country that perform HHT testing. Results typically take 3-6 weeks and a report is sent to the physician or genetic counselor who arranged for and ordered the testing.

What's The Best Way To Arrange Genetic Testing For My Family and Myself?

The first person to be tested in a family should always be someone who has a clear and definite clinical diagnosis of HHT. Genetic testing for the first person in a family will involve extensive testing of both the endoglin and ALK-1 genes and will be relatively expensive. But after a mutation is found in one family member, it is easy, and relatively inexpensive, to test other family members to see who else has inherited this same mutation.

Unfortunately, there are HHT families in which the laboratories cannot find the responsible gene mutation in the endoglin or ALK-1 gene. If genetic testing is not able to identify a mutation in a family member who clearly has HHT, it will not be useful to perform genetic testing on other family members.

The HHT Foundation strongly encourages individuals and families to arrange genetic testing through health care providers who understand all of the complexities and limitations of genetic testing for HHT. This can be done by working with one of the HHT Centers or with a genetics clinic in your area. Contact information for HHT Centers can be found at the HHT Foundation website (www.hht.org). If it is too difficult for you to travel to one of the HHT Centers, you can ask your doctor for a referral to a local genetics specialist. Genetics clinics can be found through the website of the National Society of Genetic Counselors (www.nsgc.org).

What Are The Possible Results From Genetic Testing?

The first person tested from a given family will be tested by methods that examine the complete sequence of both the endoglin and ALK-1 genes. There are 3 possible results from this analysis:

1. Positive for a "deleterious" (disease causing) mutation. This result means that the laboratory found a mutation in either endoglin or ALK-1, and that the mutation is one that is known to prevent the endoglin or ALK-1 gene from working properly. This result means that the laboratory has found the cause of HHT in the tested person. Other family members can now be tested to see if they have HHT by having testing to see if they also have this 'family specific' mutation.
2. Negative for a significant DNA sequence variation. This result means that the laboratory was not able to find a mutation in the endoglin or ALK-1 gene that could explain the tested person's HHT. Genetic testing will not be useful for determining which other family members have HHT.
3. Uncertain. The laboratory has found a variation in the DNA sequence of either the endoglin or ALK-1 gene, but cannot be certain whether or not it is the actual cause of the HHT. These kinds of gene variations are found in all genes and they are particularly common in the endoglin and ALK-1 genes. In most cases, this type of 'uncertain' result will not be useful for determining which other family members have HHT. Sometimes laboratories are able to do additional testing to try to clarify an 'uncertain' result and then are able to reclassify it as 'positive'.

For additional family members being tested to see if they have inherited a mutation already identified in a family member with HHT, there are 2 possible test results:

1. Positive for the family mutation. This person has inherited the gene mutation known to cause HHT in their family. This person has HHT.
2. Negative for the family mutation. This person has not inherited the gene mutation known to cause HHT in their family and is predicted to be unaffected by HHT and not at risk to pass it to children.

How Could Genetic Testing Fail To Find The Mutation That Causes HHT In Someone Who Clearly Has The Condition?

There are a few possible explanations why this occurs:

1. The person has HHT as a result of a mutation in endoglin or ALK-1 that cannot be detected by current testing techniques.
2. The person has HHT as a result of a mutation in a gene other than endoglin or ALK-1. The endoglin and ALK-1 genes are responsible for most cases of HHT, but there exists solid evidence that there are other rare HHT genes that have not yet been found.
3. The person who was tested does not really have HHT. Some people who have symptoms of HHT may have a different disease. Physicians who are not familiar with HHT may order testing for patients who do not actually have the condition. This is one reason why the HHT Foundation believes it is best if genetic testing is done only after a physician who is experienced with HHT has evaluated someone.

Researchers are working with HHT families in which no mutation has been found using current testing techniques in order to develop additional ways to test the already known HHT genes, as well as to identify additional HHT gene(s).

If A Physician Is Unsure Whether A Patient Has HHT, Can Genetic Testing Help Make a Diagnosis?

This is usually only helpful if a mutation in endoglin or ALK-1 has already been found in a relative who clearly has HHT. As discussed above, there are people with HHT who do not have a detectable mutation in either the endoglin or ALK-1 gene. This means that genetic testing will not determine reliably whether someone has HHT unless the responsible mutation is present and identified in another clearly affected family member. The initial diagnosis of HHT in a family should always rely on a careful and targeted clinical examination, medical history, and a detailed, extended family history taken with specific symptoms of HHT in mind.